11.2 Cellular Signaling

Life of an organism at the biochemical level can be thought of as a collection of biological events, some occurring sequentially in time and some in parallel. Each of the biological events can, in turn, be broken down into one or more signaling cascades that usually consist of multiple signaling processes separated in space and time. How a specific cell in an organism will behave depends critically on this spatio-temporal separation of signaling processes. Cellular signaling broadly refers to these highly evolved networks of signaling events and cascades that allow a cell to function.

Cellular signaling has been studied for more than 100 years now and our knowledge of its complexity at multiple levels has been greatly enhanced through advances in many di erent areas of biology.1–3 It still appears that we may have barely opened the ‘‘Pandora’s box’’ as the current knowledge seems unable to explain the beautiful richness of the complexity of life observed on land and especially in the oceans. One of the many great examples of signaling complexity manifested in nature is the dynamic camouflage ability of cuttlefish, where highly coupled signaling cascades enable these mollusks to replicate not only the color of their environment but also its visual pattern and texture (depth) onto their skin to blend in with that environment.4,5

11.2.1Types of Signaling

Any signaling network or cascade is a series of biochemical processes, where each process is initiated by the appearance of a signal which is followed by its sensing, processing and transmission as another signal or signals for the next downstream process in the signaling cascade. The signal may appear either inside or outside the cell for processing. Extracellular signals are usually sensed and processed by plasma membrane proteins. Intracellular signals are processed by soluble proteins or membrane proteins in the plasma membrane or those on the surface or cell organelles.

The spatio-temporal separation of signaling processes and cascades mentioned earlier allows one to classify signaling processes into the following types that depend on the spatial origin of the signal in an organism and its reach within the organism:

a)Endocrine signaling: In this long-range signaling, signal molecules such as hormones are released by a cell and travel long distances (via bloodstream in animals or vascular system in plants) to cause an e ect in a di erent part of the organism. Processing of sensory signals like light, taste and smell can also be considered endocrine.

b)Paracrine signaling: This is a short-range version of endocrine signaling, where the signal produced by a cell is sensed locally, e.g. neurotransmitters that are processed by proximal neurons.

c)Juxtacrine signaling: In this signaling process, the signal is membrane bound on one cell and is sensed by a receptor on the adjacent cell,

e.g. membrane proteins on a cell membrane can be sensed by a Notch protein on the neighboring cell.

d)Autocrine signaling: In this signaling process, cells release a signal molecule outside the cell, which is sensed by a membrane protein on the same cell leading to self-stimulation, e.g. breast cancer cells release transforming growth factor alpha (TGF-a) that interact with its epidermal growth factor (EGF) receptor.

e)Intracrine signaling: In this signaling process, the signal molecule is generated inside the cell and sensed by another receptor from inside the cell.

f)Electrical signaling: This specialized signaling process propagates an electrical potential along the length of the cell and occurs on a long spatial scale. The cells that use this process are the neurons of the animal nervous system, which are unusually long cells.

Any signaling cascade may be made up of one or more of the abovementioned signaling processes.

11.2.2Membrane Proteins in Signaling

The diversity of signals is immense. Chemical signals are molecules ranging greatly in size from the very small (like oxygen molecule, adrenaline, etc.), to peptides (like cytokines) and large proteins. Non-chemical signals include photons that are absorbed by cis-retinal-rhodopsin complex in the retina and initiate a cascade of processes that start in the cell and end in the brain with the perception of vision. Di erent proteins have evolved along with the signaling processes to sense this broad spectrum of signals.

Spatial separation of signaling cascades in an organism is achieved by cells expressing di erent receptors on their surface as well as inside the cell. Cell surface receptors (membrane proteins) enable signal transduction across the plasma membrane by converting an extracellular signal into one or more intracellular signaling cascades. Three main classes of membrane proteins dominate TM signal transduction:6

a)Ion-channel receptors (ICRs): These proteins are responsible for sensing neurotransmitter molecules or voltage gradients across the membrane, as upon binding to the signal molecules or sensing the membrane potential

these receptors undergo a conformational change that opens or closes a channel and allows specific ions to cross the plasma membrane.7

b)Enzyme-linked receptors (ELRs): These are a diverse class of single-pass TM proteins that contain an extracellular ligand binding site and an intracellular catalytic/enzyme-binding site with a guanylyl cyclase, phos-

phatase, serine/threonine kinase or tyrosine kinase activity. Receptor tyrosine kinases dominate this class.8

c)G protein-coupled receptors (GPCRs): These form the largest superfamily of membrane proteins that undergo ‘‘signal-specific’’ conformational changes upon activation by a diverse set of extracellular signals. These